In the pharmaceutical, health food, food and industrial fields, it has conventionally been widely carried out to prepare compositions in each of which an active ingredient is mixed with other additives.
Particularly, many active ingredients used in the pharmaceutical and health food fields have low moldability and thus an excipient is generally used as an additive in preparing compositions such as a tablet, granules, and fine granules. Among them, crystalline cellulose is widely used as an excipient for a tablet since it has high moldability as well as rapid disintegration.
When the content of an active ingredient is 20% by weight or less, its content needs to be made uniform in a tablet in order to accurately exert its pharmaceutical effect. In order to make the content of the active ingredient uniform, a method, such as a wet compression method involving mixing an active ingredient with other additives, granulating the mixture using water or the like together with a binder to make granules, further adding a lubricant and mixing, and compressing this mixture to form a tablet; or a wet granulation and tableting with extra-granular addition of disintegrant involving adding crystalline cellulose and a disintegrant to the above granules and mixing, further adding a lubricant and mixing, and compressing this mixture to form a tablet, is used. In the wet granulation and tableting with extra-granular addition of disintegrant, it is desired that granules containing an active ingredient and other additives such as crystalline cellulose and a disintegrant are not separated or segregated from each other during a mixing step or other steps passed through until forming a tablet.
On the other hand, a direct compression method is known which involves mixing an active ingredient with other additives, further adding a lubricant and mixing, and compressing this mixture to form a tablet. With regard to the direct compression method, it is difficult to ensure the content uniformity compared to the wet compression method and the wet granulation and tableting with extra-granular addition of disintegrant because it does not include any step of processing the active ingredient into granules or the like and is directly affected by the physical properties of the active ingredient. In order to reduce effects of the physical properties of an active ingredient, pulverizing the active ingredient to render its particle size small is carried out. Rendering the particle size of an active ingredient small brings about low fluidity because it reduces the weight and increases the surface adhesion. As a result, since the insufficient filling into a die occurs during tableting, variation of the tablet weight easily arises, and thus it is difficult to ensure the content uniformity of the active ingredient.
Thus, for the direct compression method, it is a challenge to reconcile the stabilization of the physical property of an active ingredient with such fluidity as to enable the tableting thereof. To ensure fluidity, additives having good fluidity are generally added. Most of them have a large average particle size. However, there is a problem that an increase in the difference between the average particle size of the active ingredient and the particle size of the additives facilitates the occurrence of separation and segregation. The following have previously been disclosed as a method for overcoming the separation and segregation.